St. John’s Wort



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Am Fam Physician. 2005 Dec 1;72(11):2249-2254.

St. John’s wort has been used to treat a variety of conditions. Several brands are standardized for content of hypericin and hyperforin, which are among the most researched active components of St. John’s wort. St. John’s wort has been found to be superior to placebo and equivalent to standard antidepressants for the treatment of mild to moderate depression. Studies of St. John’s wort for the treatment of major depression have had conflicting results. St. John’s wort is generally well tolerated, although it may potentially reduce the effectiveness of several pharmaceutical drugs.

The botanical St. John’s wort (Hypericum perforatum) is native to Europe, West Asia, and North Africa, and has been naturalized to North and South America and Australia. The Greeks and the Romans documented its medicinal use in the treatment of nerve-related disorders. In Germany, St. John’s wort is the most commonly prescribed anti-depressant. In 1984, the German Commission E designated St. John’s wort as an approved herb,1 and its safety and effectiveness are reevaluated periodically.

St. John’s wort has been used to treat a variety of conditions. It also has been suggested to alleviate symptoms of premenstrual syndrome2 and obsessive-compulsive disorder3; however, these applications have been studied less extensively. Additional studies of St. John’s wort, funded by the National Center for Complementary and Alternative Medicine, are underway.4 This review focuses solely on the use of St. John’s wort for the treatment of depression.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

St. John’s wort is recommended as a safe and effective treatment option for patients with mild to moderate depression.

A

11,16,2022

St. John’s wort cannot be recommended for patients with major or severe depression because of inconsistent evidence in clinical trials.

B

1719


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 2160 or http://www.aafp.org/afpsort.xml.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

View Table

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating References

St. John’s wort is recommended as a safe and effective treatment option for patients with mild to moderate depression.

A

11,16,2022

St. John’s wort cannot be recommended for patients with major or severe depression because of inconsistent evidence in clinical trials.

B

1719


A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 2160 or http://www.aafp.org/afpsort.xml.

Pharmacology

The main active components of St. John’s wort are thought to be hypericin and hyperforin.5 St. John’s wort also contains other common plant constituents (e.g., flavonoids and flavonoid derivatives, xanthone derivatives, amentoflavone, biapigenin, volatile oil) that may have antidepressant effects. Although additional research is needed to definitively understand the effects of these components alone and in combination, most available St. John’s wort formulations are now standardized to include hypericin (range: 0.1 to 0.4 percent) and hyperforin (range: 2.0 to 4.0 percent) because these constituents have been researched the most extensively.

Studies6 have suggested that St. John’s wort acts via inhibition of the reuptake of serotonin, dopamine, and noradrenaline, along with activation of gamma-amino-butyrate and glutamate receptors. At high dosages, hypericin is a monoamine oxidase inhibitor; however, these effects have not been demonstrated with the consumption of St. John’s wort at dosages recommended for the treatment of depression.7

The absorption and elimination of hypericin extract have been researched in healthy volunteers.8 After oral ingestion, plasma levels were measurable within two to three hours. A steep cumulative rise in plasma levels was seen during the first three days; however, a more gradual rise continued for several weeks. The elimination half-life was 24 to 48 hours.8

Effects on Depression

A Cochrane Systematic Review9 used specific criteria to examine the use of St. John’s wort for depression. Study limitations included heterogeneous diagnoses of depression, short trial durations, and low dosages of standard antidepressants in comparison trials. In all but one of the 27 clinical studies (n = 2,291) of different hypericum preparations, investigators concluded that St. John’s wort was either more effective than placebo or as effective as older pharmaceutical antidepressants in the treatment of mild to moderate depression.

More recently, 13 additional clinical trials have been published, some of which, along with a Cochrane review, are summarized in Table 1.919 In 10 of these studies, investigators found that St. John’s wort was superior to placebo11,16,2022 or as effective as standard antidepressants (e.g., amitriptyline [Elavil],10 fluoxetine [Prozac],12,13 imipramine [Tofranil],11,14 sertraline [Zoloft]15) in the treatment of mild to moderate depression. Two updated meta-analyses exploring the effectiveness of St. John’s wort for the treatment of depression are based on studies published between 1979 and 2003.23 Although their results suggest the possibility that St. John’s wort may be less effective than previously assumed, the meta-analyses indicated that St. John’s wort was significantly more effective than placebo (risk ratio for first meta-analysis: 1.97, 95% confidence interval [CI], 1.54 to 2.53; risk ratio for second meta-analysis: 1.73, 95% CI, 1.40 to 2.14).

TABLE 1

Key Studies of St. John’s Wort for Depression

Study/location

Sample/number

Agents/dosage

Outcome

Cochrane Review Linde, 19969 various locations

Systematic review of 27 studies (n = 2,291) examining the treatment of depression

St. John’s wort (350 to 1,800 mg) daily

St. John’s wort was superior to placebo and as effective as standard antidepressants.

Wheatley, 199710 United Kingdom

Moderate depressive disorder (HAM-D; n = 165)

St. John’s wort (900 mg) versus amitriptyline (Elavil; 75 mg) daily for six weeks

Both treatments were equally effective.

Philipp, 199911 Germany

Moderate depressive disorder (HAM-D; n = 263)

St. John’s wort (1,050 mg) versus imipramine (Tofranil; 100 mg) versus placebo daily

St. John’s wort was more effective than placebo and as effective as imipramine.

Harrer, 199912 Austria

Older patients with mild to moderate depression (HAM-D; n = 149)

St. John’s wort (800 mg) versus fluoxetine (Prozac; 20 mg) daily for six weeks

Both treatments were equally effective.

Schrader, 200013 Germany

Mild to moderate depression (HAM-D; n = 240)

St. John’s wort (500 mg) versus fluoxetine (20 mg) daily for six weeks

Both treatments were equally effective.

Woelk, 200014 Germany

Moderate depressive disorder (HAM-D; n = 324)

St. John’s wort (500 mg) versus imipramine (150 mg) daily for six weeks

Both treatments were equally effective.

Brenner, 200015 United States

Mild to moderate depression (HAM-D; n = 30)

St. John’s wort (900 mg) versus sertraline (Zoloft; 75 mg) daily for six weeks

St. John’s wort was at least as effective as sertraline.

Kalb, 200116 Germany

Mild to moderate major depressive disorder (HAM-D; n = 72)

St. John’s wort (900 mg) versus placebo daily for 42 days

St. John’s wort was superior to placebo at days 28 and 42.

Vorbach, 199717 multicenter

Severe depression as defined by ICD-10 (n = 209)

St. John’s wort (1,800 mg) versus imipramine (150 mg) daily for six weeks

Both treatments were equally effective (HAM-D).

Shelton, 200118 United States

Adult outpatients with major depression (baseline HAM-D score of at least 20; n = 200)

St. John’s wort (900 mg, increased to 1,200 mg if needed) versus placebo daily for four weeks

Proportion achieving response did not differ between groups.

Hypericum Depression Trial Study Group, 200219 multicenter

Adult outpatients with major depression (baseline HAM-D score of at least 20; n = 340)

St. John’s wort (900 to 1,500 mg) versus sertraline (50 to 100 mg) versus placebo daily for eight weeks

Neither sertraline nor St. John’s wort was significantly different from placebo.


HAM-D = Hamilton Rating Scale of Depression; ICD-10 = International Statistical Classification of Diseases, 10th rev.

Information from references 9 through 19.

TABLE 1   Key Studies of St. John’s Wort for Depression

View Table

TABLE 1

Key Studies of St. John’s Wort for Depression

Study/location

Sample/number

Agents/dosage

Outcome

Cochrane Review Linde, 19969 various locations

Systematic review of 27 studies (n = 2,291) examining the treatment of depression

St. John’s wort (350 to 1,800 mg) daily

St. John’s wort was superior to placebo and as effective as standard antidepressants.

Wheatley, 199710 United Kingdom

Moderate depressive disorder (HAM-D; n = 165)

St. John’s wort (900 mg) versus amitriptyline (Elavil; 75 mg) daily for six weeks

Both treatments were equally effective.

Philipp, 199911 Germany

Moderate depressive disorder (HAM-D; n = 263)

St. John’s wort (1,050 mg) versus imipramine (Tofranil; 100 mg) versus placebo daily

St. John’s wort was more effective than placebo and as effective as imipramine.

Harrer, 199912 Austria

Older patients with mild to moderate depression (HAM-D; n = 149)

St. John’s wort (800 mg) versus fluoxetine (Prozac; 20 mg) daily for six weeks

Both treatments were equally effective.

Schrader, 200013 Germany

Mild to moderate depression (HAM-D; n = 240)

St. John’s wort (500 mg) versus fluoxetine (20 mg) daily for six weeks

Both treatments were equally effective.

Woelk, 200014 Germany

Moderate depressive disorder (HAM-D; n = 324)

St. John’s wort (500 mg) versus imipramine (150 mg) daily for six weeks

Both treatments were equally effective.

Brenner, 200015 United States

Mild to moderate depression (HAM-D; n = 30)

St. John’s wort (900 mg) versus sertraline (Zoloft; 75 mg) daily for six weeks

St. John’s wort was at least as effective as sertraline.

Kalb, 200116 Germany

Mild to moderate major depressive disorder (HAM-D; n = 72)

St. John’s wort (900 mg) versus placebo daily for 42 days

St. John’s wort was superior to placebo at days 28 and 42.

Vorbach, 199717 multicenter

Severe depression as defined by ICD-10 (n = 209)

St. John’s wort (1,800 mg) versus imipramine (150 mg) daily for six weeks

Both treatments were equally effective (HAM-D).

Shelton, 200118 United States

Adult outpatients with major depression (baseline HAM-D score of at least 20; n = 200)

St. John’s wort (900 mg, increased to 1,200 mg if needed) versus placebo daily for four weeks

Proportion achieving response did not differ between groups.

Hypericum Depression Trial Study Group, 200219 multicenter

Adult outpatients with major depression (baseline HAM-D score of at least 20; n = 340)

St. John’s wort (900 to 1,500 mg) versus sertraline (50 to 100 mg) versus placebo daily for eight weeks

Neither sertraline nor St. John’s wort was significantly different from placebo.


HAM-D = Hamilton Rating Scale of Depression; ICD-10 = International Statistical Classification of Diseases, 10th rev.

Information from references 9 through 19.

Studies1719 on the use of St. John’s wort in patients with major depression have had conflicting results. According to the results of one double-blind, placebo-controlled, multi-center clinical trial18 (n = 200), St. John’s wort was effective in treating outpatients with major depression. Although the number of patients achieving remission in symptoms of depression was significantly higher with St. John’s wort therapy than with placebo (P = .02), overall remission rates were low (14.3 and 4.9 percent, respectively).

The Hypericum Depression Trial Study Group conducted a double-blind, randomized controlled trial19 (n = 340) in 12 academic and community psychiatric research clinics in the United States. Investigators found that St. John’s wort and sertraline did not differ from placebo for major depression outcomes or adverse events. The authors of an earlier study17 (n = 209) concluded that St. John’s wort was equivalent to imipramine in patients with severe depression.

Taken together, the data1022 continue to support the overall conclusions of the Cochrane review,9 as well as other published reviews,24,25 that St. John’s wort is more effective than placebo and as effective as standard antidepressants for the treatment of mild to moderate depression.

Adverse Effects, Contraindications, and Drug Interactions

In clinical trials comparing St. John’s wort with other antidepressants, the use of St. John’s wort was not associated with any serious adverse events. Authors of a systematic review26 reported an overall side-effect rate of 2.4 percent, with no severe side effects and only the expected mild side effects (i.e., gastrointestinal upset, increased anxiety, minor palpitations, photosensitivity, fatigue, restlessness, dry mouth, headache, and increased depression). Transient photosensitivity is generally the most common side effect and occurs more commonly at higher dosages.27 Use of St. John’s wort continues among a substantial number of persons without apparent serious adverse events.

Because of the possibility of developing serotonin syndrome, use of St. John’s wort in conjunction with selective serotonin reuptake inhibitors is not recommended. St. John’s wort should be used cautiously in patients with bipolar disorder because there have been a few case reports of St. John’s wort–related mania.28

Table 22940 lists the possible drug interactions that may occur with St. John’s wort. The results of one report41 suggest that induction of cytochrome (CYP) P450 3A4 activity by St. John’s wort may have a substantial impact on the effectiveness of pharmaceutical agents because at least one half of all marketed medications are metabolized via this pathway.

TABLE 2

Possible Drug Interactions with St. John’s Wort*

Agent Pathway Type of report Effect of St. John’s wort on drug levels in the blood

Amitriptyline (Elavil)

CYP P450 3A4

One-arm trial29

Decrease

Carbamazepine (Tegretol)

CYP 3A4

One-arm trial30

None

Cyclosporine (Sandimmune)

CYP 3A4

One-arm trial31

Decrease

Digoxin

CYP 3A4

Clinical trial32

Decrease

Indinavir (Crixivan)

CYP 3A4

One-arm trial33

Decrease

Irinotecan (Camptosar)

CYP 3A4

Crossover trial34

Decrease

Midazolam (Versed)

CYP3A

Clinical trial35

Decrease

Nevirapine (Viramune)

CYP 3A4

One-arm trial36

Decrease

Oral contraceptives

CYP 3A4

Clinical trial35

Decrease

Sertraline (Zoloft)

CYP P450 3A4

One-arm trial37

Decrease

Simvastatin (Zocor)

CYP 3A4

Clinical trial38

Decrease

Tacrolimus (Prograf)

CYP 3A4

One-arm trial31

Decrease

Theophylline

CYP 1A2

Case report39

Decrease

Warfarin (Coumadin)

CYP 2C9

Case report40

Decrease


CYP = cytochrome.

*—These possible interactions are based on preliminary results and may or may not prove to be clinically meaningful.

Information from references 29 through 40.

TABLE 2   Possible Drug Interactions with St. John’s Wort*

View Table

TABLE 2

Possible Drug Interactions with St. John’s Wort*

Agent Pathway Type of report Effect of St. John’s wort on drug levels in the blood

Amitriptyline (Elavil)

CYP P450 3A4

One-arm trial29

Decrease

Carbamazepine (Tegretol)

CYP 3A4

One-arm trial30

None

Cyclosporine (Sandimmune)

CYP 3A4

One-arm trial31

Decrease

Digoxin

CYP 3A4

Clinical trial32

Decrease

Indinavir (Crixivan)

CYP 3A4

One-arm trial33

Decrease

Irinotecan (Camptosar)

CYP 3A4

Crossover trial34

Decrease

Midazolam (Versed)

CYP3A

Clinical trial35

Decrease

Nevirapine (Viramune)

CYP 3A4

One-arm trial36

Decrease

Oral contraceptives

CYP 3A4

Clinical trial35

Decrease

Sertraline (Zoloft)

CYP P450 3A4

One-arm trial37

Decrease

Simvastatin (Zocor)

CYP 3A4

Clinical trial38

Decrease

Tacrolimus (Prograf)

CYP 3A4

One-arm trial31

Decrease

Theophylline

CYP 1A2

Case report39

Decrease

Warfarin (Coumadin)

CYP 2C9

Case report40

Decrease


CYP = cytochrome.

*—These possible interactions are based on preliminary results and may or may not prove to be clinically meaningful.

Information from references 29 through 40.

Given the induction of CYP 3A4, concurrent use of St. John’s wort may reduce the effectiveness of oral contraceptives. In a study35 of 12 healthy premenopausal women who received an oral contraceptive along with 900 mg of St. John’s wort daily in three divided doses, researchers noted a shorter estrogen half-life and increased breakthrough bleeding. Women using oral contraceptives should be counseled regarding possible breakthrough bleeding and might consider a barrier method of contraception when taking St. John’s wort.35

Additional study is needed to establish if and how St. John’s wort interacts with specific pharmaceutical agents. Experience to date suggests few clinically significant interactions. Until the results of ongoing studies on this matter have been published, the medications listed in Table 22940 should be considered to have potential interactions and should be monitored when used concurrently with St. John’s wort. Family physicians should query all patients about the use of St. John’s wort and other herbal agents.

Dosage

Findings suggest that 900 mg of St. John’s wort (450 mg two times daily or 300 mg three times daily) is needed to reduce symptoms of depression.8,10,17 Because plasma levels continue to show a gradual rise over several weeks, the full clinical effect of St. John’s wort may take two to four weeks to manifest.

Final Comment

St. John’s wort represents an effective therapy for the treatment of mild to moderate forms of depression. Standardized formulations are available for $10 to $25 for a one-month supply. It is important to emphasize that not all St. John’s wort products are systematically standardized. Drug interactions with St. John’s wort have been demonstrated in a variety of pharmacologic studies, although the clinical importance of these observations is uncertain given the widespread use of this agent. Table 3 outlines the effectiveness, safety, tolerability, dosage, and cost of standardized St. John’s wort formulations.

TABLE 3

Key Points About St. John’s Wort

Effectiveness

Effective for the treatment of mild to moderate depression

Insufficient evidence to establish effectiveness for the treatment of major depression

Adverse effects

Most common*: transient photosensitivity

Less common: gastrointestinal upset, increased anxiety, minor palpitations, photosensitivity, fatigue, restlessness, dry mouth, increased depression

Dosage

Standardized pills: 900 mg daily (divided into two or three doses)

Cost

$10 to $25 for a 30-day supply of standardized hypericum

Bottom line

Generally safe, well-tolerated herbal medicine for the treatment of mild to moderate depression


*—Occurs in less than 3 percent of patients.

†—Estimated cost to the pharmacist based on average wholesale prices in Red Book. Montvale, N.J.: Medical Economics Data, 2005. Cost to the patient will be higher, depending on prescription filling fee.

TABLE 3   Key Points About St. John’s Wort

View Table

TABLE 3

Key Points About St. John’s Wort

Effectiveness

Effective for the treatment of mild to moderate depression

Insufficient evidence to establish effectiveness for the treatment of major depression

Adverse effects

Most common*: transient photosensitivity

Less common: gastrointestinal upset, increased anxiety, minor palpitations, photosensitivity, fatigue, restlessness, dry mouth, increased depression

Dosage

Standardized pills: 900 mg daily (divided into two or three doses)

Cost

$10 to $25 for a 30-day supply of standardized hypericum

Bottom line

Generally safe, well-tolerated herbal medicine for the treatment of mild to moderate depression


*—Occurs in less than 3 percent of patients.

†—Estimated cost to the pharmacist based on average wholesale prices in Red Book. Montvale, N.J.: Medical Economics Data, 2005. Cost to the patient will be higher, depending on prescription filling fee.

The Authors

SILVANA LAWVERE, PH.D., is a postdoctoral fellow in the Department of Clinical Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute in Buffalo, N.Y. Dr. Lawvere obtained her Ph.D. from the School of Medicine and Biomedical Sciences, State University of New York (SUNY), Buffalo.

MARTIN C. MAHONEY, M.D., PH.D., F.A.A.F.P., is chair of the Department of Clinical Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, and associate professor in the Departments of Family Medicine and Social & Preventive Medicine at SUNY, Buffalo. Dr. Mahoney received his medical degree from SUNY, Buffalo, where he also completed a family practice residency program and a faculty development fellowship.

Address correspondence to Martin C. Mahoney, M.D., Ph.D., Department of Clinical Prevention, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute–Carlton 307, Elm and Carlton Streets, Buffalo, NY 14263 (e-mail: Martin.Mahoney@roswellpark.org). Reprints are not available from the authors.

Author disclosure: Nothing to disclose.

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Members of various family medicine departments develop articles for “Complementary and Alternative Medicine.” This is one in a series coordinated by Sumi Sexton, M.D.



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